Journal article

Structure and function of lysosomal phospholipase A2 and lecithin: cholesterol acyltransferase

Alisa Glukhova, Vania Hinkovska-Galcheva, Robert Kelly, Akira Abe, James A Shayman, John JG Tesmer

Nature Communications | NATURE PUBLISHING GROUP | Published : 2015

Abstract

Lysosomal phospholipase A2 (LPLA2) and lecithin:cholesterol acyltransferase (LCAT) belong to a structurally uncharacterized family of key lipid-metabolizing enzymes responsible for lung surfactant catabolism and for reverse cholesterol transport, respectively. Whereas LPLA2 is predicted to underlie the development of drug-induced phospholipidosis, somatic mutations in LCAT cause fish eye disease and familial LCAT deficiency. Here we describe several high-resolution crystal structures of human LPLA2 and a low-resolution structure of LCAT that confirms its close structural relationship to LPLA2. Insertions in the α/β hydrolase core of LPLA2 form domains that are responsible for membrane intera..

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Grants

Awarded by US National Institutes of Health (NIH)


Awarded by American Heart Association Pre-Doctoral Fellowship


Awarded by EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT


Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE


Awarded by NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES


Awarded by Veterans Affairs


Funding Acknowledgements

GM/CA CAT and LS CAT staff members at Argonne Photon Source for their help with data collection. Michael Won for extensive LCAT crystallization screening and Dr Jennifer Cash for advice and support with mammalian cell culture. This work was supported by the US National Institutes of Health (NIH) grants HL086865 (J.J.G.T.) and AR056991 (J.A.S.), a Merit Review Award from the Department of Veterans Affairs (J.A.S.) and an American Heart Association Pre-Doctoral Fellowship 13PRE16880003 and Rackham Graduate Student Research Grant (A.G.).